Process for the manufacture of hmg-coa reductase inhibitory mevalonic acid derivatives

ABSTRACT

The invention relates to a process for the manufacture of a compound of formula  
                 
 
or a salt, especially a pharmaceutically acceptable salt with a base, thereof or a lactone thereof wherein the element   represents —CH 2 —CH 2 — or —CH═CH— and R represents a cyclic radical.

The invention relates to a process for the manufacture of HMG-CoAreductase inhibitors, to process steps, to novel intermediates and tonovel catalysts.

HMG-CoA reductase inhibitors (also calledβ-hydroxy-β-methylglutaryl-co-enzyme-A reductase inhibitors and alsocalled statins) are understood to be those active agents which may bepreferably used to lower the lipid levels including cholesterol in bloodand can be used e.g. for the prevention or treatment of hyperlipidemiaand artheriosclerosis.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds which are selected from the group consisting of atorvastatin,cerivastatin, fluvastatin, lovastatin, pitavastatin (formerlyitavastatin), pravastatin, rosuvastatin, and simvastatin, or, in eachcase, a pharmaceutically acceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those agents which have beenmarketed, most preferred is fluvastatin, atorvastatin, pitavastatin,especially the Calcium salt thereof, or simvastatin or apharmaceutically acceptable salt thereof.

Atorvastatin of formula

is disclosed and claimed in U.S. Pat. No. 5,273,995.

Cerivastatin of formula

is disclosed and claimed in U.S. Pat. No. 5,177,080.

(+)-(5S,3R)-Form of fluvastatin of formula

is disclosed and claimed in U.S. Pat. No. 5,345,772.

Lovastatin of formula

is disclosed and claimed in U.S. Pat. No. 4,231,938.

Pitavastatin of formula

is disclosed and claimed in U.S. Pat. No. 5,856,336.

Pravastatin of formula

is disclosed and claimed in U.S. Pat. No. 4,410,629.

Rosuvastatin of formula

is disclosed and claimed in U.S. Pat. No. 5,260,440,

Simvastatin of formula

is disclosed and claimed in U.S. Pat. No. 4,444,784.

The structure of the active agents identified hereinbefore orhereinafter by generic or tradenames may be taken from the actualedition of the standard compendium “The Merck Index” or from databases,e.g. Patents International or LifeCycle Patents International,respectively, (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference. Any person skilled in theart is fully enabled to identify the active agents and, based on thesereferences, and is likewise enabled to manufacture and test thepharmaceutical indications and properties in standard test models, bothin vitro and in vivo.

Acidic representatives of HMG-Co-A reductase inhibitors have beenlaunched are being developed as salts, for example, fluvastatin assodium salt and pitavastatin as calcium salt.

The corresponding active ingredients or a pharmaceutically acceptablesalts thereof may also be used in form of a solvate, such as a hydrateor including other solvents, used for crystallization.

Essentially, statins comprise a cyclic core element and a side chainelement of formula

(a 3,5-dihydroxy-hept-6-enoic acid moiety) that might form acorresponding lactone partial structure of formula

(a 3,5-dihydroxy-heptanoic acid derivative) that might form acorresponding lactone partial structure of formula

In said side chain elements (A) or (C), respectively, the 3,5-syn diolstructure and the R-configuration at C-3 are essential features, ascorresponding statins with this specific element exhibit the highestbiological activity.

The objective of the present invention is to provide an enantioselectivesynthesis of compounds of formula (I) resulting in high yields andmoreover guaranteeing a minimization of the ecological pollution of theenvironment, being economically attractive, e.g. by using less reactionsteps in the reaction sequence for the manufacture of compounds offormula I, and leading to largely enantiomerically pure target productsand to products of high crystallisability. Furthermore, anotherobjective of the present invention is to provide a process that can becarried out in a larger scale and can thus be used for a correspondingproduction process. Furthermore, there is a need to avoid any separationof any stereoisomers.

Surprisingly, the process of the present invention clearly meets theabove objectives. The process relates to an enantioselective synthesisby using essentially the so-called transfer hydrogenation approach. Forexample, an enantiomer excess (ee) of a compound of formula (I) of ≧95%,preferably ≧98% and most preferably ≧99% can be achieved.

The invention relates to a process for the manufacture of a HMG-CoAreductase inhibitory mevalonic acid derivative of formula (Ia)

or a salt, especially a pharmaceutically acceptable salt with a base,thereof or a lactone thereof wherein

the element represents

—CH₂—CH₂— or —CH═CH— and

R represents a cyclic residue.

A salt of a compound of formula (I) is, for example, a salt with a base,preferably a corresponding pharmaceutically acceptable salt thereof.

A lactone of a compound of formula (I) is represented by formulae (Ia)and (Ib)

Corresponding cyclic residue R comprises a cyclic residue selected fromthe group consisting of

Extensive experimental evaluations surprisingly resulted in a processsequence for the manufacture that meets the above criteria showing theindicated advantages.

The process as disclosed in Bioorganic & Medicinal Chemistry Letters 9(1999) 2977-2982 for the manufacture of pitavastatin (NK 104) requiresthe formation of a racemic erythro-β,δ-dihydroxyester that is hydrolysedto form the corresponding acid. With α-methylbenzylamine adiastereomeric mixture of resulting salts are formed that need to beresolved into the different diastereomeric salts. The clear disadvantageof this approach is that half of the material needs to be destroyed.Accordingly, the process of the present invention can be carried outwithout such a diastereomeric resolution procedure.

The process for the manufacture of a compound of formula

or a salt thereof or a lactone thereof, wherein the element

represents —CH₂—CH₂— or —CH═CH— and R represents a cyclic residue,according to the present inventions is characterized by

(a) reacting a compound of formula (IIa)

wherein R¹, R² and R³, independently of one another, represents phenylthat is un-substituted or substituted by one or more substituentsselected from the group consisting of C₁-C₇alkyl, hydroxy, C₁-C₇alkoxy,C₂-C₈alkanoyl-oxy, halogen, nitro, cyano, and CF₃, and R⁴ is analiphatic, cycloaliphatic, araliphatic or aromatic residue;

with a compound of formula R—CH(═O) (IIb) wherein R represents a cyclicresidue; and

(b) reducing a resulting compound of formula (IIc)

wherein R and R⁴ have the meanings as defined above; in the presence ofa reducing agent selected from the group consisting of a compound offormulae (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″),and (IId′″″″)

wherein

M is Ru, Rh, Ir, Fe, Co or Ni;

L₁ is hydrogen;

L₂ represents an aryl or aryl-aliphatic residue;

Hal is halogen;

R⁵ is an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl oraryl-aliphatic residue, which, in each case, may be linked to a polymer;

each of R⁶ and R⁷, independently, is an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aryl or aryl aliphatic residue;

each of R⁸ and R⁹ is phenyl or R⁸ and R⁹ form together with the carbonatom to which they are attached a cyclohexane or cyclopentane ring; and

R¹⁵ is H, halogen, amino, nitro or C₁-C₇alkoxy;

wherein any aromatic residue of a compound of formula (IId), (IId′),(IId″), (IId′″), (IId″″), (IId′″″), (IId″″″) or (IID′″″″) isunsubstituted or substituted;

wherein for compounds of formula (IId″), (IId′″), (IId″″), (IId′″″),(IId″″″) or (IID′″″″) also combinations with (R)— or (S)—BINAP arepossible; and

(c) condensing a resulting compound of formula (IIe)

wherein R and R⁴ have the meanings as defined above,

with a compound of formula (II f)

wherein R¹⁶ represents an aliphatic residue, and

(d) reducing a resulting compound of formula (IIg)

wherein R and R¹⁶ have the meanings as defined above, and

(e) hydrolysing a resulting compound of formula (IIh)

wherein R and R¹⁶ have the meanings as defined above, and

(f) isolating a resulting compound of formula (I) or a salt thereof;

and, if desired, converting a resulting free acid of formula (I) into asalt thereof or into a lactone of formula (Ia) or (Ib), respectively, orconverting a resulting lactone of a formula (Ia) or (Ib) into an acid offormula (I) or a salt thereof, or converting a resulting compound offormula (I) wherein the element

represents —CH═CH— into a compound of formula (I) wherein the element

represents —CH₂—CH₂—.

The general terms used hereinbefore and hereinafter have the followingmeanings, unless defined otherwise.

C₁-C₇Alkyl is for example methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl or a corresponding pentyl, hexyl orheptyl residue. C₁-C₄alkyl, especially methyl or tert-butyl ispreferred.

C₁-C₇Alkoxy is for example methoxy, ethoxy, n-propyloxy, isopropyloxy,n-butyloxy, isobutyl-oxy, sec-butyloxy, tert-butyloxy or a correspondingpentyloxy, hexyloxy, or heptyloxy residue.

C₁-C₄alkoxy is preferred. Especially preferred is methoxy andtert-butoxy.

C₂-C₈Alkanoyl in C₂-C₈alkanoyl-oxy is in particular acetyl, propionyl,butyryl, isobutyryl or pivaloyl. C₂-C₅Alkanoyl is preferred.

Halogen is in particular halogen with an atomic number up to andincluding 35, i.e. fluorine, chlorine or bromine, and in a broader senseincludes iodine. Fluorine or chlorine is preferred.

An aliphatic hydrocarbon residue is, for example, C₁-C₇alkyl,C₂-C₇alkenyl or secondarily C₂-C₇alkynyl.

C₂-C₇Alkenyl is in particular C₃-C₇alkenyl and is, for example,2-propenyl or 1-, 2- or 3-butenyl. C₃-C₅alkenyl is preferred.

C₂-C₇-Alkynyl is in particular C₃-C₇alkynyl and is preferably propargyl.

A cycloaliphatic residue is, for example, a C₃-C₈cycloalkyl or,secondarily, C₃-C₈cycloalkenyl.

C₃-C₈Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

C₃-C₈Cycloalkenyl is in particular C₃-C₇cycloalkenyl and is preferablycyclopent-2-en-yl and cyclopent-3-enyl, or cyclohex-2-en-yl andcyclohex-3-en-yl.

A cycloaliphatic-aliphatic residue is, for example,C₃-C₈cycloalkyl-C₁-C₇alkyl, preferably C₃-C₆-cycloalkyl-C₁-C₄alkyl.Preferred is cyclopropylmethyl.

An araliphatic residue is in particular phenyl-C₁-C₇alkyl, alsophenyl-C₂-C₇alkenyl or phenyl-C₂-C₇alkynyl.

An aromatic residue is, for example, a carbocyclic or heterocyclicaromatic residue, in particular phenyl or in particular an appropriate5- or 6-membered and monocyclic residue which has up to four identicalor different hetero atoms, such as nitrogen, oxygen or sulfur atoms,preferably one, two, three or four nitrogen atoms, an oxygen atom or asulfur atom. Appropriate 5-membered heteroaryl residues are, forexample, monoaza-, diaza-, triaza-, tetraaza-, monooxa- ormonothia-cyclic aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, furyl and thienyl, while suitable appropriate6-membered residues are in particular pyridyl.

Pyrrolyl is, for example, 2- or 3-pyrrolyl. Pyrazolyl is 3- or4-pyrazolyl. Imidazolyl is 2- or 4-imidazolyl. Triazolyl is, forexample, 1,3,5-1H-triazol-2-yl or 1,3,4-triazol-2-yl. Tetrazolyl is, forexample, 1,2,3,4-tetrazol-5-yl, furyl is 2- or 3-furyl and thienyl is 2-or 3-thienyl, while suitable pyridyl is 2-, 3- or 4-pyridyl.

Appropriate multicyclic residues are anthracenyl, phenanthryl,benzo[1,3]-dioxole or pyrenyl. An aryl residue may be monosubstituted bye.g. NH₂, OH, SO₃H, CHO, or di-substituted by OH or CHO and SO₃H.

Any aromatic residue is preferably unsubstituted or substituted, forexample, by one or more, e.g. two or three, residues e.g. those selectedfrom the group consisiting of C₁-C₇alkyl, hydroxy, C₁-C₇alkoxy,C₂-C₈alkanoyl-oxy, halogen, nitro, cyano, and CF₃.

Polymers may be polystyrene (PS), cross-linked PS (J), polyethyleneglycol (PEG) or a silica gel residue (Si). Examples are NH—R¹⁵ whereinR¹⁵ is C(O)(CH₂)_(n)—PS or C(O)NH(CH₂)_(n)—PS; and—O—Si(R¹⁴)₂(CH₂)_(n)R¹⁶ wherein n is 1 to 7, R¹⁴ is C₁-C₆alkyl, e.g.ethyl, and R¹⁶ is a PS, J, PEG or Si (obtainable by Aldrich,Switzerland).

In formula formula (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″),(IId″″″) or (IID′″″″) the following significances are preferredindependently, collectively or in any combination or sub-combination:

M is Ru, Rh, Ir, preferably Ru.

L₂ is isopropylmethyibenzene, benzene, hexamethylbenzene, mesitylene,preferred is isopropylmethylbenzene.

R⁵ is 2- or 3- or 4-pyridyl, 4-chloro-4-phenoxy-phenyl,4-phenoxy-phenyl, 5-di(m)ethylamino-1-naphthyl, 5-nitro-1-naphthyl, 2-,3-, 4-nitrophenyl, 4-vinylphenyl, 4-biphenylyl, 9-anthracenyl, 2, 3 or 4hydroxyphenyl, tolyl, phenanthryl, benzo[1,3]-dioxole,dimethyl(naphthalene-1-yl)-amine, mono to tristrifluoromethylphenyl,chrysenyl, perylenyl or pyrenyl or 2-phenylethene.

Each of R⁶ and R⁷, independently, are phenyl, 4-methylphenyl or3,5-dimethylphenyl, preferred is phenyl.

Each of R⁸ and R⁹ is phenyl or cyclohexyl or substituted phenyl,preferably is phenyl.

Preferred Hal is chloro.

Preferred R¹⁵ is H.

L₁ is as defined above.

In a preferred aspect, the invention provides a process for theproduction of a compound of formula I′a or I′b

The reactions described above and below in the variants are carried out,for example in the absence or, customarily, in the presence of asuitable solvent or diluent or a mixture thereof, the reaction, asrequired, being carried out with cooling, at room temperature or withwarming, for example in a temperature range from about −80° C. up to theboiling point of the reaction medium, preferably from about −10° toabout +200° C., and, if necessary, in a closed vessel, under pressure,in an inert gas atmosphere and/or under anhydrous conditions.

Preferably, in the process according to the present invention compoundsof formulae (IIa), (II c), (IIe), (IIf), (IIg) and (IIh) are used,wherein R⁴ or R¹⁶, respectively, represent C₁-C₄alkyl, especially methylor ethyl or most preferably tert-butyl.

Step a):

In reaction Step (a), the reaction of a compound of formula (IIa) with acompound of formula (IIb) is carried out in a suitable inert solvent,such as a nitrile, especially acetonitrile or propionitrile, and in atemperature range from, for example, from −78° C., to the boiling pointof the solvent, preferably at the boiling point of the solvent.

Step (b):

Reaction Step (b) is an asymmetric transfer hydrogenation, especiallywhen using a chiral Ru(II) catalyst of formula (IId) and a hydrogendonor.

Step (b) is carried out in a suitable inert solvent such as an ether,e.g. tetrahydrofuran, an ester, such as ethylacetate, an nitrile,especially acetonitrile, a formamide, especially dimethylformamide, andin a temperature range from, for example, from −78° C., to the boilingpoint of the solvent, preferably at room temperature.

Preferred catalysts are following compounds

wherein L₁ is hydrogen and L₂ represents an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aryl or araliphatic residue; Hal is halogen;R⁵, R⁶ and R⁷, independently of one another, represents an aliphatic,cycloaliphatic, cycloaliphatic-aliphatic, aryl or araliphatic residue;wherein, in each case, any aromatic residue of a compound of formulae(IId), (IId′) and (IId″) is unsubstituted or substituted;

Preferred Ru (II) catalysts of formula (IId) are those wherein L₁ ishydrogen and L₂ is isopropylphenyl, R⁵ is tolyl.

A preferred hydrogen donor is, for example, NEt₃/H₃PO₂/H₂O,diphenylsilan/MeOH or a system comprising 2-propanol, 3-pentanol, ormost preferably HOOCH in the presence of an amine, such astriethylamine, DBU or other tertiary amines. The hydrogen donor may alsobe used as inert solvent, especially 2-propanol and most preferablyHCOOH. An alternative hydrogen donor is 2-propanol in the presence ofvarious catalysts and base, e.g. Ru[(tS,2S)-p-TsNCH(C₆H₅)CH(C₆H₅)NH](η⁶-p-cymene) and base or “in situ”[Ru(η⁶-p-cymene)Cl₂]₂ with chiral ligand (R,R— or S,S-TsDPEN,amino-alcohol) and base. The preferred bases are: t-BuOK, KOH or i-PrOK.

A preferred hydrogen donor is, for example, a system comprising HOOCH inthe presence of an amine, such as triethylamine, or most preferably2-propanol. The hydrogen donor may also be used as inert solvent,especially HCOOH and most preferably 2-propanol.

Step (b) can also be carried out by hydrogenating with hydrogen in thepresence of a catalyst of formula (IId′) or (IId″), (IId″), (IId′″),(IId″″), (IId′″″), (IId″″″) or (IID′″″″), respectively. A suitable inertsolvent is e.g. an ether, such as tetrahydrofuran, an ester, such asethylacetate, or an alcohol, such as a C₁-C₄alkanol, for example,isopropanol.

Preferred Hal is chloro.

Step (c):

Condensation Step (c) is carried out in the presence of a condensationsystem and in a suitable inert solvent, such as an ether, especiallytetrahydrofuran or tert-butyl-ethyl ether, and in a temperature rangefrom, for example, from −78° C., to the boiling point of the solvent,preferably at room temperature.

A suitable condensating system is, for example, a base, such as analkane alkalimetal, especially butyl lithium, or a hydride, e.g. sodiumhydride, or a mixture thereof. Especially preferred is the use of thecondensation system butyl lithium in the presence of diisopropylamine.

Step (d):

A preferred reduction agent is, for example, a hydride, for example, analkalimetal borohydrid, especially sodium borohydride, preferably in thepresence of a di-C₁-C₇alkyl-C₁-C₇alkoxy-borane, most preferablydiethyl-methoxy-borane.

The reduction is carried out in an inert solvent, such as an ether,preferably tetrahydrofuran, and at low temperatures, for example, from−78° to 0° C., preferably at −78° C. To split a corresponding boronicester the reaction mixture is then oxidized with an oxidizing agent,such as a peroxide, especially, hydrogen peroxide. The oxidation iscarried out in an inert solvent, such as an ether, preferablytetrahydrofuran, and in a temperature range from, for example, from 0°C., to the boiling point of the solvent, preferably in a range of 0° to20° C.

Step (e):

The saponification Step (e) is carried out, for example, by treating theester of formula (IIh) with a strong base, such as an alkali metalhydroxide, preferably NaOH, or with Ca(OH)₂ and acidifying the resultingreaction mixture.

Step (f):

The isolation Step (f) of a compound of formula (I) is carried outaccording to conventional isolation methods, such as by crystallizingthe resulting compound of formula (I) from the reaction mixture or bychromatography of the reaction mixture.

Inert solvents are those that do not react with the correspondingreactants.

The present invention likewise relates to a novel compound of formula(IIc). Especially preferred are compounds of formula (IIc), wherein R isa group of formula

the element

represents —CH═CH—, and R₄ is C₁-C₄alkoxy, especially methoxy or ethoxyor tert-butoxy.

The present invention likewise relates to a novel compound of formula(IIc). Especially preferred are compounds of formula (IIc), wherein R isa group of formula

the element

represents —CH═CH—, and R⁴ is C₁-C₄alkoxy, especially methoxy or ethoxyor tert-butoxy.

It is known from the art that asymmetric transfer hydrogenation using aRu (II) catalyst (esp. a Noyori catalyst) is carried out in the absenceof water and under inert gas conditions. Surprisingly, the transferhydrogenation step according to the present invention can be run in awater containing solvent system and in the absence of an inert gas. Thismeans that the reaction is successful even though the solvent usedcomprised water (e.g. 3% by Karl-Fischer).

Furthermore, the compound of formula (IIc) could—in view of theesterified carboxy group—be a ligand of the Ru (II) catalyst as well.Surprisingly, it has been proven that a compound of formula (IIc) doesnot form a ligand to the Ru catalyst.

It is known that quinoline moieties are desactivating the hydrogenationcatalysts. Especially, in case of the manufacture of compound of (I)being pitavastatin, the person skilled in the art would expect that thequinoline group desactivates the Ru catalyst. Surprisingly, theasymmetric transfer hydrogenation step according to the presentinvention is successfully carried out without that the catalyst offormulae (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″) or(IId′″″″) is being desactivated.

Accordingly, the present invention also relates to reaction step (b),especially when using a Ru(II) catalyst of formulae (IId), (IId′) or(IId″), respectively.

-   -   wherein M, L₁, L₂, R⁸ and R⁹ are as defined above and R⁵is a        group of formula        wherein

n is 0, 1, 2, 3, 4, 5, 6 or 7;

X is O or S;

R¹⁰ is polystyrol;

R¹¹ is silica gel;

R¹² is cross-linked polystyrol;

R¹³ is polyethylene-glycol;

R¹⁴ is C₁-C₆alkyl; and

m is 1, 2 or 3.

The following compounds of formula (IId), (IId′), (IId″″″) or (IId″″″)wherein L₁, L₂ and R⁵ are as defined above, are preferred:

Compounds of formula (IId), (IId′), (IId″″″) or (IId″″″) may be preparedby reacting a compound of formula VII

wherein R⁵, R⁸ and R⁹ are as defined above, with [MCl₂(p-cymene)]₂ inconventional manner. The hydrogenation may be carried out in a suitableinert solvent, such as an ether, e.g. tetrahydrofuran, an ester, such asethylacetate, a halogenated solvent, such as methylenchioride,supercritical CO₂, ionic liquids, a nitrile, especially acetonitrile, anamide, such as dimethylformamide or dimethylacetamide and in atemperature range from, for example, from −78° C., to the boiling pointof the solvent, preferably at room temperature.

Preferred catalysts of formula (IId) are those, wherein L₁ is hydrogenand L₂ represents phenyl or phenyl substituted by one, two, three, fouror five alkyl residues, especially by once by isopropyl such as4-isopropyl-phenyl, and R⁵ represents phenyl or phenyl substituted byone, two, three, four or five alkyl residues, especially phenyl, tolyl,3,5-dimethylphenyl, or 2,3,4,5,6-pentamethyl-phenyl. Especiallypreferred is the catalyst of formula (IId) or (Id′), wherein L₁ ishydrogen, L₂ is isopropylphenyl, and R⁵ is tolyl.

The present invention likewise relates to preferred catalysts of formula(IId) being those, wherein L₁ is hydrogen and L₂ represents phenyl orphenyl substituted by one, two, three, four or five alkyl residues,especially by once by isopropyl such as isopropyl-phenyl, and R₅represents a residue selected from the group consisting of 2- or 3- or4-pyridyl, 4-choro-4-phenoxy-phenyl, 4-phenoxy-phenyl,5-di(m)ethylamino-1-naphthyl, 5-nitro1l-naphthyl, 2-, 3-, 4-nitrophenyl,4-vinylphenyl, 4-biphenylyl, 2-phenyl-ethen and 9-anthracenyl.

Especially preferred are those catalysts of formula (IId), wherein theligands L₁ and L₂ have the S or R configuration and/or wherein thecorresponding phenyl rings attached to the 1,2-diaminoethyl moiety arein the R,R-configuration or S,S-configuration.

Preferred catalysts of formula (IId′) and (IId′″) are those, wherein Halis each case is chloro; R⁶ and R⁷, in each case, represents phenyl orphenyl substituted by one or more C₁-C₇alkyl, especially3,5-dimethylphenyl. The present invention likewise relates tocorresponding compounds of formula (IId′). Especially preferred arethose catalysts of formula (IId′), wherein the BINAP moiety has the R—or S-configuration.

Preferred catalysts of formula (IId″) and (IId″″) are those, whereinHal, in each case, is chloro; R³ and R⁷, in each case, represents phenylor phenyl substituted by one or more C₁-C₇alkyl, especially3,5-dimethylphenyl. The present invention likewise relates tocorresponding compounds of formula (IId″″) and (IId′″″). Especiallypreferred are those catalysts of formula (IId″″) and (IId′″″), whereinthe BINAP moiety has the R— or S-configuration. Most preferred arecorresponding compounds of formula (IId′″″) and (IId′″″)

Likewise preferred are compounds of formula

The present invention likewise relates to the novel compounds, e.g.starting materials or intermediates, respectively, as described in theWorking Examples part.

The present invention likewise relates to the concrete products directlyobtained by the process sequence or by the single process steps,especially the corresponding products that are in an essentiallyenantiomerically pure form.

The conversion of an acid of formula (I) into a salt is carried out in amanner known per se.

Thus, for example, a salt with a base of compounds of the formula I isobtained by treating with a base. Salts can be converted into the freecompounds in a customary manner, and salts with a base can be converted,for example, by treating with a suitable acid agent to the free acid.

The conversion of an acid of formula (I) into a corresponding lactone offormula (Ia) or (Ib), respectively, is carried out in the presence of anacid, preferably a mineral acid, in a suitable, e.g. protic or aproctic,solvent, such as ethanol or acetonitrile. Depending on the acid, theconversion is carried out in a temperature range, for example, from −78°to the boiling point of the solvent. Most preferably, H₃PO₄ inacetonitrile at 60° C. is used.

The conversion of a lactone of formula (Ia) or (Ib), respectively, intoa salt of the acid of formula (I) is carried out, for example, in amixture of a protic solvent, e.g. ethanol, and water, by using analkalimetall hydroxide, such as LiOH, NaOH or Ca(OH)₂. Alternatively,the lactone can be hydrolysed by using an alkalimetall hydroxide, suchas LiOH, NaOH and the resulting salt can be converted into the calciumsalt of the acid of pitavastatin by addition of an aqueous solution ofCaCl₂ in water.

A variant to the process according to the present invention comprisesthe direct formation of a lactone of a compound of formula (I). Theformation of said lactone can be carried out by treating a compound offormula (I) or (IIh) with an acid, such as a mineral acid, preferablewith H₃PO₄.

The conversion of a resulting compound of formula (I) wherein theelement

represents —CH═CH— into a compound of formula (I) wherein the element

represents —CH—CH₂— is carried out by selectively hydrogenating thedouble bond —CH═CH—, especially with an appropriate reduction agent, forexample, by catalytic hydrogenation in the presence of a hydrogenationcatalyst, for example, a Ruthenium catalyst, such as(Ru(cod)(nu-3-(2-methylally))2, by reduction with hydrogen in thepresence of a hydrogenation catalyst or with a hydride, for example, ahydride which, if desired, may be complex, such as a hydride formed froman element of the 1st and 3rd main groups of the periodic table of theelements, for example borohydride or aluminohydride, for example lithiumborohydride, lithium aluminium hydride, diisobutylaluminium hydride (anadditional reduction step using alkali metal cyanoborohydride, such assodium cyanoborohydride, may be necessary), and also diborane.

Instead of converting a resulting compound of formula (I) wherein theelement

represents —CH═CH— into a compound of formula (I) wherein the element

represents —CH₂—CH₂ 13 , the hydrogenation of the double bond —CH═CH—can be effected, with compounds of formulae (IIe), (IIg) or (IIh),respectively, e.g. in addition to reaction steps (c), (d) or (e),respectively.

The process for the manufacture of compounds of formula (I) and saltsthereof can be, for example, illustrated by means of the followingreaction scheme for the manufacture of pitavastatin:

The process for the manufacture of compounds of formula (I) and saltsthereof can be, for example, illustrated by means of the followingreaction scheme for the manufacture of fluvastatin:

WORKING EXAMPLES

Manufacture of Starting Material for Pitavastatin:

Preparation of (3-ethoxycarbonyl-3-oxopropyl)triphenyl phosphoniumchloride

According to Literature: C. M. Moorhoff; J.C.S. Perkin Trans I, 1987(1997)

To a solution of ethyl-4-chlor-acetoacetat (16.46 g, 100 mmol) in 50 mlanhydrous toluene is added triphenylphosphine (26.25 g, 100 mmol) underargon atmosphere at room temperature and stirred for 4 days. Thesuspension is filtered and washed with 3×30 ml of toluene. Thecolourless crystals are dried in vacuum to give(3-ethoxycarbonyl-3-oxopropyl) triphenyl phosphonium chloride. MS:426.88

Example 1 a) Preparation of ethyl3-oxo-4-(triphenylphosphoranylidene)butanoate

To a solution of (3ethoxycarbonyl-3oxopropyl) triphenyl phosphoniumchloride (11 g, 25.77 mmol) in 100 ml dichlormethane is added within 30minutes (min) under vigorous stirring sodium carbonate (3.38 g, 27.36mmol) in 100 ml water at room temperature and stirred for 4 hours (h).The yellow organic phase is separated, washed with 30 ml water and driedover anhydrous sodium sulfate. The solvent is evaporated and the oilyresidue is dried in vacuum to maintain a waxy mass. After addingdiethylether the wax crystallizes to form slight yellow crystals of3-oxo-4-(triphenylphosphoranylidene)butanoate. MS : 390.43

¹H-NMR (CDCl₃, 400 MHz):

δ=7.56 (m,6H, ortho H-phenyl), 7.44 (m, 3H,para H-phenyl), 7.35 (m,6H,meta H-phenyl), 4.08 (q, 2H, OCH ₂CH₃), 3.72 (d, 1H, H-4), 3.26 (d,2H, H-2), 1.17 (t, 3H), OCH₂CH ₃)

b) 5(2-Cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoicacid ethyl ester

The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (4.82 g, 12.36mmol) is solved under argon atmosphere in 100 ml acetonitrile. Undervigorous stirring2-cyclopropyl-4-(4-fluoro-phenyl)-quinoline-3-carbaidehyde (3 g, 10.3mmol) is added in 5 portions and then heated to reflux. After 50 h thereaction is cooled to room temperature. The slight brown solvent isevaporated and the residue is dried under vacuum to obtain a brown waxyoil. Chromatography over silica gel with hexane:ethylacetate (4:1/v:v)give a yellow oil of5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic acidethyl ester. MS: 403.45

c) rac5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoicacid ethyl ester

85.8 mg (0.21 mmol) of5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic acidethyl ester are solved in 10 ml ethanol under argon atmosphere andcooled to −15° C. Sodiumborhydride (8.58 mg, 0.22 mmol) is added undervigorous stirring. During the reaction time the mixture became slightlyyellow. After 3 h the reaction is allowed to rise to room temperatureand stirred for another 1.5 h. Then the mixture is quenched with 15 mlof a saturated ammonium chloride solution. After extraction withdiethylether (3×15 ml), the combined organic layers are washed withwater (15 ml), dried over sodium sulfate, filtered and evaporated invacuum to give a yellow oil of rac5-[2-cylopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoicacid ethyl ester. MS: 405.47

HPLC-Analytius: Chiracel-OD 10 μm, length: 250 mm, internal-dm: 4.6 mm;isokratic n-hexane: 2-propanol 96:4; flowrate:0.6 ml/min; columntemp:35° C.; UV detection wavelength: 230 nm; chrom.time: 45 min;inject.volume:10 μl (1.022 mg/ml in n-hexane:2-propanol 96:4)

Ret.Time 1: 16.17 min; 51.52 % (area)

Ret.Time 2: 18.00 min; 48.48 % (area)

d) Procedure for the enantioselective transfer hydrogenation of(E)-5-]2-Cycloropyl-4-(4-fluoro-phenyl)-guinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester

I: A mixture of(E)-5-]2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-oxo-pent-4-enoic-acid-ethylester(105.8 mg, 0.262 mmol) and Ru[(1R,2R)-p-TsNCH(C₆H₅)CH(C₆H₅)NH](η⁶-p-cymene) (6.2 mg, 0.104 mmol) in 2-propanol (2.6 ml) isstirred at 23° C. for 72 h. The reaction mixture is concentrated underreduced pressure. The residue is purified by flash chromatography onsilica gel using a 4:1 hexane-MTBE (methyl-tert-butyl-ether) mixture aseluent to afford of(E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester.

II: A solution of(E)-5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-oxo-pent-4-enoic-acid-ethylester(1.6 g, 3.97 mmol), Ru[(1R,2R)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂]Cl(η⁶-p-cymene)(12.6 mg, 0.02 mmol) and a mixture of HCOOH (1.095 g, 23.8 mmol)/NEt₃(0.963 g, 9.52 mmol) is heated in DMF (6.0 ml) at 50° C. for 20 h. Afterthat the solution is diluted with MTBE (5 ml) and neutralised withNaHCO₃ (4 ml). Standard aquous work-up with NaCl solution and extractionwith MTBE and removel of the solvent give the crude product.Chromatography on silica gel using a 4:1 hexane-MTBE mixture as eluentto afford of(E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester.

¹H NMR (400 MHz, CDCl₃): 7.96 (d, ²J: 8.4 Hz, 1H), 7.60 (t, ²J: 6.6 Hz,1H), 7.38-7.28 (m, 2H), 7.25-7.15 (m, 4H), 6.61 (d, ²J: 16.3 Hz, 1H),5.65 (dd, ² ²J: 16.2, 5.7 Hz, 1H), 4.57-4.51 (m, 1H), 4.17 (q, ²J: 7.1Hz, 2H), 3.10 (br s, 1H), 2.44-2.37 (m, 1H), 2.36 (t, ²J: 9.4 Hz, 2H),1.41-1.25 (m, 2H), 1.29 (t, ²J: 7.2 Hz, 3H), 1.04 (dd, ²J: 8.1, 2.8 Hz,2H).

¹³C NMR (100 MHz, CDCl₃): 172.2, 163.6, 161.1, 160.7, 146.9, 144.4,138.2, 133.4, 132.0, 131.9, 131.9, 131.8, 129.0, 128.9, 126.5, 126.1,125.5, 115.5, 115.3, 68.8, 41.1, 16.1, 14.2, 10.4, 10.3. MS: 405.47

Literature for the preparation of the catalyst: Haack, K-J.; Hashiguchi,S.; Fujii, A.; Ikaiya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997,36, 285-288.

e)(E)-(S)-7-[2-Clyopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester

To a solution of diisopropylamine (0.93 g, 9.20 mmol) in tetrahydroturan(THF) (10 ml) at 0° C. is added n-BuLi (5.55 ml, 8.88 mmol of a 1.6 Msolution in hexane) over 10 min. After 30 min the solution is cooled to−78° C. and t-butyl acetate (1.03 g, 8.88 mmol) is added over 10 min.After 30 min the resulting solution at −78° C. is transferred to asolution of(E)-5-[2-cycloproyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester(0.90 g, 2.22 mmol) in THF (11 ml) at 0° C. The solution is stirred 3 hat room temperature (RT). A NH₄Cl solution (3 ml) is added. The mixtureis poured into water (5 ml) and extracted with MTBE (50 ml). Thecombined organic extracts are dried over Na₂SO₄, filtered, concentrated,and the residue purified by flash chromatography (hexane/MTBE 5:1) toafford ketoester(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-pheny)-quinolin-3yl]-5hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester. MS: 475.57

f)(E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester

To a solution of ketoester(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester (0.80 g, 1.68 mmol) in THF (20 ml) and MeOH (4 ml)at −78° C. is added diethylmethoxyborane (2.10 ml of a 1 M solution inTHF, 2.096 mmol). After 1 h NaBH₄ (0.127 g, 3.36 mmol) is added. Afteran additional 3 h at −78° C. pH 7 buffer (5 ml) is added followed byMeOH (6 ml). After 10 min a solution of MeOH (6 ml) and 30% aqu. H₂O₂ (6ml) is added slowley. The cold bath is removed and the solution stirredfor 1.5 h. The mixture is poured into NaHCO₃ (60 ml) and extracted withCH₂Cl₂ (3×50 ml). The organic extracts are dried over Na₂SO₄, filtered,and concentrated. The residue is dissolved in hot EtOAc (10 ml),filtered and stirred for 12 h at RT. After filtration diol(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester is obtained. MS: 477.58

g)(E)-(3S,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3.5-dihydroxy-hept-6-enoicacid tert-butyl ester

To a cooled (−35° C.) solution of Me₄NHB(OAc)₃ (1.38 g, 5.26 mmol) inMeCN/AcOH (15 ml, 1:1) is added a solution of ketoester(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester (0.50 g, 1.05 mmol) in CH₃CN (2 ml). The mixtureis stirred at −35° C. for 3 h and at 0° C. for 30 min before a solutionof potassium sodium tartrate (10 ml) is added. After 10 min thesuspension is poured into CH₂Cl₂ (30 ml) and a solution of Na₂CO₃ (7 ml)is carefully added. The organic layer is separated and the aquous layeris extracted with CH₂Cl₂ (2×50 ml). The combined organic extracts aredried over Na₂SO₄, filtered, concentrated, and the residue is purifiedby flash chromatography (hexane/MTBE 1:1) or crystallization(ethylacetate=EtOAc) to afford diol(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5dihydroxy-hept-6-enoicacid tert-butyl ester. MS: 477.58

h)(E)-(3R,5S)-7-[2-Cycloprogyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3.5-dihydroxy-hept-6-enoicacid calcium salt

To a solution of diol(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester (1.0 g, 2.09 mmol) in EtOH (5 ml) is added anaquous solution of NaOH (10 ml, 1 M) and the resulting suspension isstirred until the ester disappeaered. After completion of the hydrolysisaqueous HCl (15 ml, 1 M) is added and the solvent is removed in vacuum.Then CH₂Cl₂ (10 ml) is added and the organic layer is separated. Theaqueous layer is extracted with CH₂Cl₂ (2×30 ml) and the combinedorganic extracts are removed in vacuum. The residue is dissolved in H₂O(20 ml) and a solution of CaCl₂ (8 ml, 0.1 M) is added dropwise. Thereaction solution is stirred overnight and the resulting whiteprecipitate is collected by filtration to obtain(E)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoicacid calcium salt MS: 880.98

Manufacture of Starting Material for Fluvastatin:

i.(E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoicacid ethyl ester

The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (5.0 g, 12.8mmol) is solved under argon atmosphere in 100 ml acetonitrile. Undervigorous stirring3-(4-Fluoro-phenyl)-1-isopropyl-1H-indole-2-carbaldehyde (4.2 g, 10.7mmol) is added in 5 portions and then heated to reflux. After 50 h thereaction is cooled to room temperature. The slight brown solvent isevaporated and the residue is dried under vacuum to obtain a brown waxyoil. Chromatography over silica gel with hexane:ethylacetate (4:1/v:v)give a yellow oil of(E)-5-[3-(4-Fluoro-phenyl-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoicacid ethyl ester. MS: 393.46

j.(E)-(S)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pent-4-enoicacid ethyl ester

A solution of(E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoicacid ethyl ester (2.0 g, 5.08 mmol),Ru[(1R,2R)-p-TsNCH(C₆H₅)CH(C₆H₅)NH₂]Cl(η⁶-p-cymene) (12.8 mg, 0.025mmol) and a mixture of HCOOH (1.40 g, 30.5 mmol)/NEt₃ (1.23 g, 12.2mmol) is heated in DMF (8.0 ml) at 50° C. for 21 h. After that thesolution is diluted with MTBE (5 ml) and neutralised with NaHCO₃ (4 ml).Standard aquous work-up with NaCl solution and extraction with MTBE andremovel of the solvent give the crude product. Chromatography on silicagel using a 4:1 hexane-MTBE mixture as eluent to afford of(E)-(S)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pent-4-enoicacid ethyl ester. MS: 395.48

k.(E)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester

To a solution of diisopropylamine (0.96 g, 9.53 mmol) in tetrahydrofuran(THF) (10 ml) at 0° C. is added n-BuLi (6.32 ml, 10.12 mmol of a 1.6 Msolution in hexane) over 10 min. After 30 min the solution is cooled to−78° C. and t-butyl acetate (1.17 g, 10.12 mmol) is added over 10 min.After 30 min the resulting solution at −78° C. is transferred to asolution of(E)-(S)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pent-4-enoicacid ethyl est (1.0 g, 2.53 mmol) in THF (12 ml) at 0° C. The solutionis stirred 3 h at room temperature (RT). A NH₄Cl solution (3 ml) isadded. The mixture is poured into water (5 ml) and extracted with MTBE(50 ml). The combined organic extracts are dried over Na₂SO₄, filtered,concentrated, and the residue purified by flash chromatography(hexane/MTBE 5:1) to afford ketoester(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester. MS: 465.57

l.(E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester

To a solution of ketoester(E)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester (1.0 g, 2.15 mmol) in THF (22 ml) and MeOH (4 ml)at −78° C. is added diethylmethoxyborane (2.70 ml of a 1 M solution inTHF, 2.682 mmol). After 1 h NaBH₄ (0.163 g, 4.30 mmol) is added. Afteran additional 3 h at −78° C. pH 7 buffer (6 ml) is added followed byMeOH (7 ml). After 10 min a solution of MeOH (6 ml) and 30% aqu. H₂O₂ (6ml) is added slowley. The cold bath is removed and the solution stirredfor 15 h. The mixture is poured into NaHCO₃ (70 ml) and extracted withCH₂Cl₂ (3×50 ml). The organic extracts are dried over Na₂SO₄, filtered,and concentrated. The residue is dissolved in hot EtOAc (10 ml),filtered and stirred for 12 h at RT. After filtration diol(E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester is obtained. MS: 467.58

m.(E)-(3S,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester

To a cooled (−35° C.) solution of Me₄NHB(OAc)₃ (1.38 g, 5.26 mmol) inMeCN/AcOH (15 ml, 1:1) is added a solution of ketoester(E)-(S)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-5-hydroxy-3-oxo-hept-6-enoicacid tert-butyl ester (0.50 g, 1.07 mmol) in CH₃CN (2 ml). The mixtureis stirred at −35° C. for 3 h and at 0° C. for 30 min before a solutionof potassium sodium tartrate (10 ml) is added. After 10 min thesuspension is poured into CH₂Cl₂ (30 ml) and a solution of Na₂CO₃ (7 ml)is carefully added. The organic layer is separated and the aquous layeris extracted with CH₂Cl₂ (2×50 ml). The combined organic extracts aredried over Na₄SO₄, filtered, concentrated, and the residue is purifiedby flash chromatography (hexane/MTBE 1:1) or crystallization(ethylacetate=EtOAc) to afford diol(E)-(3S,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoicacid tert-butyl ester. MS: 467.58

n. Sodium(E)-(3R,5S)-7-[3-(4-fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoate

To 30 g of esterE)-(S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-hept-6enoicacid tert-butyl ester in 150 ml of ethanol is added under stirring 63 mlof sodium hydroxide solution while maintaining the temperature below 12°C. The solution is stirred for 1 hour, the mixture is concentrated at 25mm Hg and 45° C., then 220 ml of water are added, destillation iscontinued to a remaining volume of 100 ml , then 280 ml of water areadded and the solution is washed with a total of 450 ml of MTBE in 3portions. The aquous layer is concentrated at 25 mm Hg and 45° C. to avolume of about 200 ml, 150 ml water are added, and the clear aquoussolution is Iyophylized over 3 days. MS: 433.21

1. A process for the manufacture of a compound of formula

or a salt thereof or a lactone thereof, wherein the element

represents —CH₂—CH₂— or —CH═CH— and R represents a cyclic residue,according to the present inventions is characterized by (a) reacting acompound of formula (IIa)

wherein R¹, R² and R³, independently of one another, represents phenylthat is un-substituted or substituted by one or more substituentsselected from the group consisting of C₁-C₇alkyl, hydroxy, C₁-C₇alkoxy,C₂-C₈alkanoyl-oxy, halogen, nitro, cyano, and CF₃, and R⁴ is analiphatic, cycloaliphatic, araliphatic or aromatic residue; with acompound of formula R—CH(═O) (IIb) wherein R represents a cyclicresidue; and (b) reducing a resulting compound of formula (IIc)

wherein R and R⁴ have the meanings as defined above; in the presence ofa reducing agent selected from the group consisting of a compound offormulae (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″),and (IId′″″″)

wherein M is Ru, Rh, Ir, Fe, Co or Ni; L₁ is hydrogen; L₂ represents anaryl or aryl-aliphatic residue; Hal is halogen; R⁵ is an aliphatic,cydoaliphatic, cycloaliphatic-aliphatic, aryl or ary-aliphatic residue,which, in each case, may be linked to a polymer; each of R⁶ and R⁷,independently, is an aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aryl or aryl-aliphatic residue; each of R⁸ andR⁹ is phenyl or R⁸ and R⁹ form together with the carbon atom to whichthey are attached a cyclohexane or cyclopentane ring; and R¹⁵ is H,halogen, amino, nitro or C₁-C₇alkoxy; wherein any aromatic residue of acompound of formula (IId), (IId′), (IId″), (IId′″), (IId″″), (IId′″″),(IId″″″) or (IID′″″″) is unsubstituted or substituted; wherein forcompounds of formula (IId″), (IId′″), (IId″″), (IId′″″), (IId″″″) or(IID′″″″) also combinations with (R)— or (S)—BINAP are possible; and (c)condensing a resulting compound of formula (IIe)

wherein R and R⁴ have the meanings as defined above, with a compound offormula (IIf)

wherein R¹⁶ represents an aliphatic residue, and (d) reducing aresulting compound of formula (IIg)

wherein R and R¹⁶ have the meanings as defined above, and (e)hydrolysing a resulting compound of formula (IIh)

wherein R and R¹⁶ have the meanings as defined above, and (f) isolatinga resulting compound of formula (I) or a salt thereof; and, if desired,converting a resulting free acid of formula (I) into a salt thereof orinto a lactone of formula (Ia) or (Ib), respectively, or converting aresulting lactone of a formula (Ia) or (Ib) into an acid of formula (I)or a salt thereof, or converting a resulting compound of formula (I)wherein the element

represents —CH═CH— into a compound of formula (I) wherein the element

represents —CH₂—CH₂—.
 2. A process according to claim 1, wherein acompound of formulae (IIa), (IIc), (IIe), (IIg) and (IIh) is used,wherein R⁴ or R¹⁶, respectively, represent C₁-C₄alkyl, especially methylor ethyl or most preferably tert-butyl.
 3. A process for the manufactureof a compound of formula (IIe)

wherein R and R⁴ have the meanings as defined above, characterized byreducing a resulting compound of formula (IIc)

wherein R and R⁴ have the meanings as defined above; in the presence ofa reducing agent of formula

wherein M, L₁, L₂, R⁸ and R⁹ are as defined above and R⁵ is a group offormula

wherein n is 0 , 2, 3, 4, 5, 6 or 7; X is O or S; R¹⁰ is polystyrol; R¹¹is silica gel; R¹² is cross-linked polystyrol; R¹³ ispolyethylene-glycol; R¹⁴ is C₁-C₆alkyl; and m is 1, 2 or
 3. 4. Acompound of formula (IId), wherein L₁ is hydrogen and L₂ representsphenyl or phenyl substituted by one, two, three, four or five alkylresidues, especially by once by isopropyl such as 4-isopropyl-phenyl,and R₅ represents a residue selected from the group consisting of 2- or3- or 4-pyridyl, 4-chloro-4-phenoxy-phenyl, 4-phenoxy-phenyl,5-di(m)ethylamino-1-naphthyl, 5-nitro-1-naphthyl, 2-, 3-, 4-nitrophenyl,4-vinylphenyl, 4-biphenylyl, 9-anthracenyl, 2,3-, 4-hydroxyphenyl,tolyl, phenanthryl, benzo[1,3]-dioxole,dimethyl(naphthalene-1-yl)-amine, mono to tristrifluoromethylphenyl,chrysenyl, perylenyl and pyrenyl or 2-phenylethene.
 5. A compound offormula (IId″) and (IId′″), wherein Hal is each case is chloro; R₆ andR₇, in each case, represents phenyl or phenyl substituted by one or moreC₁-C₇alkyl, especially 3,5-dimethylphenyl.
 6. A compound of formula(IId″″) and (IId′″″), wherein Hal is each case is chloro; R₆ and R₇, ineach case, represents phenyl or phenyl substituted by one or moreC₁-C₇alkyl, especially represents 3,5-dimethylphenyl.
 7. A compound offormula (IId′″″) and (IId″″″), wherein Hal is each case is chloro; R⁶and R⁷, in each case, represents phenyl or phenyl substituted by one ormore C₁-C₇alkyl, especially represents 3,5-dimethylphenyl.